1-bromo-4-chloro-2-(difluoromethoxy)benzene

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-5-chlorophenol (1 g, 4.8 mmol) in DMF/water (45 mL/5 mL) was added sodium chlorodifluoroacetate (1.95 g, 12.0 mmol) and cesium carbonate (3.14 g, 9.64 mmol), and the reaction mixture was heated to 100° C. for 4 hours. The reaction mixture was cooled and diluted with TBME (20 mL) and water (20 mL). The organic layer was collected, washed with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.21 g, 98%), which was used without further purification. The reaction mixture was cooled The organic layer was collected washed with saturated aqueous NaHCO3 solution, brine dried over Na2SO4 concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chloro-2-(difluoromethoxy)bromobenzene (Preparation 27, 200 mg, 0.63 mmol) in THF (6 mL) was added bis-neopentylglycolatodiboron (149 mg, 0.660 mmol), potassium acetate (191 mg, 1.88 mmol) and Pd(dppf)Cl2 (23 mg, 0.031 mmol). The reaction mixture was heated to reflux for 4 hours before cooling and diluting with EtOAc and water. The organic layer was collected, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in acetone (6 mL) and treated with a solution of oxone (1.64 g, 2.54 mmol) in water (6 mL). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with diethyl ether (10 mL) and water (5 mL). The organic layer was collected, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-15% diethyl ether in DCM to afford the title compound. The reaction mixture was heated to reflux for 4 hours before cooling The organic layer was collected washed with brine dried over Na2SO4 concentrated in vacuo The residue was dissolved in acetone (6 mL) The organic layer was collected washed with brine dried over Na2SO4 concentrated in vacuo The residue was purified eluting with 0-15% diethyl ether in DCM

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A microwave vial was charged with N-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate E) (130 mg, 0.229 mmol), 1-bromo-4-chloro-2-(difluoromethoxy)benzene (Intermediate J) (118 mg, 0.458 mmol) and Pd(dppf)Cl2DCM (37.4 mg, 0.046 mmol). Dioxane (1145 μl) and t-butanol (1145 μl) were added to the reaction vial followed by sodium carbonate in water (362 μl, 0.687 mmol, 1.9 M). The vial was purged with nitrogen and sealed. The mixture was stirred and sonicated for 5 min. The resulting light red mixture was then heated in a microwave at 100° C. for 30 min LC/MS indicated complete conversion of boronic ester to the desired product. The reaction was cooled to rt and filtered through a fritted funnel with an aid of DCM (15 mL). The filtrate was acidified with 2N aqueous HCl to a pH of about 1. After stirring for 5 min at room temperature, the product was extracted with DCM (2×20 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated to afford a dark oil. MS (ESI): 639.8 [M+Na]+ The vial was purged with nitrogen sealed sonicated for 5 min The reaction was cooled to rt filtered through a fritted funnel with an aid of DCM (15 mL) After stirring for 5 min at room temperature the product was extracted with DCM (2×20 mL) washed with brine dried over MgSO4 filtered concentrated to afford a dark oil

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the procedure disclosed in Published PCT Patent Application No. WO2011/003065 A2. To a solution of 2-bromo-5-chlorophenol (4.34 g, 20.92 mmol) (the oil from above) in N,N-dimethylformamide (21.8 mL, 20.9 mmol) was added sodium chlorodifluoroacetate (7.34 g, 48.1 mmol), cesium carbonate (9.54 g, 29.3 mmol), and water (2.18 mL, 20.9 mmol). The reaction was stirred at 100° C. for 16 h. The reaction was cooled to room temperature and partitioned between EtOAc (100 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2×70 mL). The organic layers were combined and washed with water (2×50 mL), 10% aq. citric acid (1×30 mL), brine, dried over MgSO4, filtered, and concentrated to afford 1-bromo-4-chloro-2-(difluoromethoxy)benzene (4.35 g, 16.9 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.30 (dd, J=2.3, 8.6 Hz, 1H), 7.37 (t, J=73 Hz, 1H), 7.49 (dt, J=2.40, 0.81 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H). The title compound was prepared The reaction was cooled to room temperature partitioned between EtOAc (100 mL) and water (50 mL) The aqueous layer was extracted with EtOAc (2×70 mL) washed with water (2×50 mL), 10% aq. citric acid (1×30 mL), brine dried over MgSO4 filtered concentrated